5-aryltetrazole compounds and compositions thereof

ABSTRACT

Abstract of the Disclosure 
     ABSTRACT5-ARYLTETRAZOLES COMPOUNDS AND COMPOSITIONS THEREOFThe present invention relates to 5-Aryltetrazole Compounds, compositions comprising an effective amount of a 5-Arytetrazole Compound, and methods for treating an inflammation disease, a reperfusion disease, or hyperuricemia in an animal in need thereof comprising administering to the animal an effective amount of a 5-Aryltetrazole compound.

Detailed Description of the Invention CROSS REFERENCE TO RELATEDAPPLICATIONS

This Application is a Continuation of Application 10/620619 filed onJuly 17, 2003. Application 10/620619 is a Continuation-in-part ofApplication 10/197609 filed on July 18, 2002. The disclosure of each ofthe aforementioned applications is incorporated herein by reference inits entirety.

GOVERNMENTAL SUPPORT

The research leading to the invention was supported, at least in part,by a grant from: the National Institute of General Medical SciencesGrant No. 1R43 GM63274-01A1; the National Heart, Lung, and BloodInstitute Grant No. 1R43HL70342-01; the National Institute of GeneralMedical Sciences Grant No. 2R44GM59017-02; and the National Institute ofGeneral Medical Sciences Grant No. 1R43GM59017-01. Accordingly, the U.S.Government may have certain rights in the invention.

1. FIELD OF THE INVENTION

The present invention relates to 5-Aryltetrazole Compounds, compositionscomprising an effective amount of a 5-Aryltetrazole Compound, andmethods for treating or preventing an inflammation disease, areperfusion disease, or hyperuricemia comprising administering to ananimal in need thereof an effective amount of a 5-AryltetrazoleCompound.

2. BACKGROUND OF THE INVENTION

The level of xanthine oxidase ("XO") in an animal increases markedly(>400-fold in bronchoalveolar fluid in pneumonitis) during inflammation,ischemia-reperfusion injury, and atherosclerosis. Particularly, due tothe spillover of tissue XO into the circulation, plasma levels of XO maybe detected in an animal experiencing adult respiratory distresssyndrome, ischemia-reperfusion injury, arthritis, sepsis, hemorrhagicshock, and other inflammatory conditions. Inflammation-induces histaminerelease by mast cells and basophils also enhances the activity of XO.

Superoxide radical (O₂ ⁻) can be generated by xanthine oxidase and NADPHoxidase from the partial reduction of molecular oxygen. Neutrophils andmacrophages are known to produce O₂ ⁻ and hydrogen peroxide (H₂O₂),which normally are involved in the killing of ingested or invadingmicrobes (T. Oda et al., Science, 244: 974-976). Under physiologicconditions Xo is ubiquitously present in the form of a xanthinedehydrogenase (XDH). XDH is a molybdenum iron-sulfur flavindehydrogenase that uses NAD⁺ as an electron acceptor to oxidize purines,pyrimidines, pteridins, and other heterocyclic nitrogen-containingcompounds. In mammals, XDH is converted from the NAD⁻ dependentdehydrogenase form to the oxygen-dependent oxidase for, either byreversible sulfhydryl oxidation or irreversible proteolytic modification(S. Tan et al., Free Radic. Biol. Med. 15: 407-414). Xanthine oxidasethen no longer uses NAD⁺ as an electron acceptor, but transferselectrons onto oxygen, generating O₂ ⁻, H₂O₂, and hydroxyl radical (OH)as purines are degraded to uric acid (J. M. McCord et al., New Engl. J.Med. 312: 159-163; R. Miesel et al., Inflammation, 18: 597-612).Inflammatory activation converts XDH to XO, mainly by oxidizingstructurally important thiolates. Inflammation also markedlyup-regulates the conversion of xanthine dehydrogenase (T. D. Engerson etal., J. Clin. Invest. 79: 1564-1570).

Inhibition of XO activity blocks the formation of O₂ ⁻ and prevents lossof purine nucleotides, and is therefore salutary in a variety of shockand ischemia reperfusion disorders. Pharmacologic inhibition of XO canalso be beneficial by blocking the pro-inflammatory effect of O₂ ⁻ ongene expression (M. D. Schwartz et al., Am. J Respir. Cell. Mol. Biol.,12: 434-440). O₂ ⁻ has been implicated in the nuclear translocation ofNF-kappa B and the expression of NF-icB-dependent genes. In micesubjected to hemorrhagic shock, depletion of XO by a tungsten-enricheddiet decreased mononuclear mRNA levels of IL-113 and TNF-a. Similarresults were obtained after pharmacologic inhibition of XO by in vivoadministration of allopurinol. A vicious cycle can be created by oxidantstress, in which O₂ ⁻ induction of pro-inflammatory cytokines results ingreater XDH to XO conversion, and thus more O₂ ⁻ production. Thissuggests that XO inhibitors can exert important anti-inflammatoryactions by interrupting this process at multiple points, in particular,by blocking pro-inflammatory gene expression.

Pharmacologic inhibition of XO can also be beneficial in hemorrhagicshock by preserving the intracellular nucleotide pool. Under conditionsof energetic failure, induced by hypoxia or by oxidant-inducedpoly(ADP-ribose) synthetase activation, high energy phosphatenucleotides are sequentially degraded to inosine monophosphate,xanthine, and hypoxanthine. In the presence of XO and molecular oxygen,xanthine and hypoxanthine degrade to uric acid, thereby depleting thepurine pool. The loss of available purines with which to form ATPaccelerates the loss of intracellular energetics and contributes to cellnecrosis and organ failure. XO inhibitors block this terminaldegradative pathway and permit the cell to recover and reestablishadequate stores of high energy phosphate nucleotides. In a canine modelof severe hemorrhagic shock, pre-treatment with allopurinol resulted ina 6-fold increase in survival (J. W. Crowell et al., Am. J. Phys. 216:744-748). When the administration of allupurinol exerted no benefit.Infusion of the purine base hypoxanthine after the onset of shocksimilarly provided no benefit. When allupurinol and hypoxanthine afterthe onset of shock similarly provided no benefit. When allopurinol andhypoxanthine were co-infused, however, there was a dramatic increase insurvival (no survival in control group at 16 hours post-shock vs. a 40%survival in the treated group at 48 hours). Similar results wereobtained in a canine model of hemorrhagic shock in which allupurinolsignificantly improved survival, whereas a cocktail of free-radicalscavengers (superoxide dismutase, catalase, dimethylsulfoxide, and alphatocopherol) had no effect (D. Mannion, et al., circ. Shock, 42: 39-43).Thus, XO blockade appears to be beneficial by three independentmechanisms: blockade of O₂ ⁻ formation; inhibition of O₂ ⁻ mediatedpro-inflammatory gene expression; and preservation of the nucleotidepool available for ATP formation.

Accordingly, there is a clear need for compounds that inhibit the levelsof xanthine oxidase in an animal and, accordingly, that are useful fortreating or preventing an inflammation disease, a reperfusion disease,or hyperuricemia.

Citation of any reference in Section of this application is not anadmission that the reference is prior art to the application.

3. SUMMARY OF THE INVENTION

The invention encompasses compounds having the formula (Ia):

and pharmaceutically acceptable salts and hydrates thereof, wherein:

R₁ is CO₂R₄;

each R₂ is independently -halo, -NO₂, -CN, -OH, -N(R₅)(R₅), -OR₅,-C(O)R₅, -OC(O)R₅, -C(O)NHC(O)R₅, -(C₁-C₁₀)alkyl, -(C₂-C₁₀)alkenyl,-(C₂-C₁₀)alkynyl, -(C₃-C₁₀)cycloalkyl, -(C₈-C₁₄)bicycloalkyl,-(C₅-C₁₀)cycloalkenyl, -(C₃-C₁₀)heterocycle, -phenyl, -naphthyl,-benzyl, -CO₂R₅ -C(O)OCH(R₅)(R₅), -NHC(O)R₅, -NHC(O)NHR₅, -C(O)NHR₅,-OC(O)R₅, -OC(O)OR₅, -SR₅, -S(O)R₅, or -S(O)₂R₅;

R₃ is -H, -halo, -NO₂, -CN, -OH, -N(R₅)(R₅), -O(CH₂)_(m)R₅, -C(O)R₅,-C(O)N(R₅)(R₅), -C(O)NH(CH₂)_(m)(R₅), -OCF₃, -benzyl, -CO₂CH(R₅)(R₅),-(C₁-C₁₀)alkyl, -(C₂-C₁₀)alkenyl, -(C₂-C₁₀)alkynyl, -(C₃-C₁₀)cycloalkyl,-(C₈-C₁₄)bicycloalkyl, -(C₅-C₁₀)cycloalkenyl, -naphthyl,-(C₃-C₁₀)heterocycle, -CO₂(CH₂)_(m)R₅, -NHC(O)R₅, -N(R₅)C(O)R₅,-NHC(O)NHR₅, -OC(O)(CH₂)_(m)CHR₅R_(5,) -OC(O)OR₅, -SR₅, -S(O)R₅,-S(O)₂R₅, -S(O)₂NHR₅, or

R₄ is -(C₅)heteroaryl, -(C₆)heteroaryl, phenyl, naphthyl, or benzyl;

each R₅ is independently -H, -CF_(3,) -(C₁-C₁₀)alkyl, -benzyl,adamantly, -morpholinyl, -pyrrolidyl, -pyrridyloxide,-pyrrolidinyldione, -piperdidyl, -(C2-C₁₀)alkenyl,

each R₆ is independently -H, -halo, -NO₂, -CN, -OH, -CO₂H,-N((C₁-C₁₀)alkyl(C₁-C₁₀)alkyl), -O(C₁-C₁₀)alkyl, -C(O)(C₁-C₁₀)alkyl,-C(O)NH(CH₂)_(m)(C₁-C₁₀)alkyl, -OCF₃, -benzyl,-CO₂(CH₂)_(m)CH((C₁-C₁₀)alkyl(C₁- C₁₀)alkyl), -C(O)H, -CO₂(C₁-C₁₀)alkyl,-(C₁-C₁₀)alkyl, -(C₂-C₁₀)alkenyl, -(C₂-C₁₀)alkynyl, -(C₃-C₁₀)cycloalkyl,-(C₈-C₁₄)bicycloalkyl, -(C₅-C₁₀)cycloalkenyl, -(C₅)heteroaryl,-(C₆)heteroaryl, -phenyl, naphthyl, -(C₃-C₁₀)heterocycle,-CO₂(CH₂)_(m)(C₁-C₁₀)alkyl, -CO₂(CH₂)_(m)H, -NHC(O)(C₁-C₁₀)alkyl,-NHC(O)NH(C₁-C₁₀)alkyl, -OC(O)(C₁-C₁₀)alkyl, -OC(O)O(C₁-C₁₀)alkyl,-SO₂NHR₅, or -SO₂NH₂;

n is an integer ranging from 0 to 4;

each m is independently an integer ranging from 0 to 8; and

each p is independently an integer ranging from 0 to 5.

A compound of formula (Ia) or a pharmaceutically acceptable salt orhydrate thereof is useful for treating or preventing an inflammationdisease, a reperfusion disease, or hyperuricemia in an animal.

The invention also relates to pharmaceutical compositions comprising aneffective amount of a compound of formula (Ia) or a pharmaceuticallyacceptable salt or hydrate thereof; and a pharmaceutically acceptablecarrier or vehicle. These composition are useful for treating orpreventing an inflammation disease, a reperfusion disease, orhyperuricemia in an animal.

The invention also relates to compounds of formula (Ib):

and pharmaceutically acceptable salts and hydrates thereof, wherein:

R₁ is -H, -CO₂R₄, -C(O)R₅, or -C(O)N(R₅)(R₅);

R₂ is -(C₁-C₁₀)alkyl or -O(C₁-C₁₀)alkyl;

R₄ is -(C₅)heteroaryl, -(C₆)heteroaryl, phenyl, naphthyl, or benzyl; and

each R₅ is independently -H, -CF₃, -(C₁-C₁₀)alkyl, -benzyl,-(C₂-C₁₀)alkenyl, -(C₂-C₁₀)alkynyl, -(C₃-C₁₀)cycloalkyl,-(C₈-C₁₄)bicycloalkyl, -(C₃-C₁₀)heterocycle.

A compound of formula (Ib) or a pharmaceutically acceptable salt orhydrate thereof is useful for treating or preventing an inflammationdisease, a reperfusion disease, or hyperuricemia in an animal.

The invention also relates to pharmaceutical compositions comprising aneffective amount of a compound of formula (Ib) or a pharmaceuticallyacceptable salt or hydrate thereof; and a pharmaceutical compositionscomprising an effective amount of a compound of formula (Ib) or apharmaceutically acceptable salt or hydrate thereof; and apharmaceutically acceptable carrier or vehicle. These compositions areuseful for treating or preventing an inflammation disease, a reperfusiondisease, or hyperuricemia in an animal.

The invention further relates to methods for treatment or preventing aninflammation disease, comprising administering to an animal in needthereof an effective among of a compound of formula (Ia) or (Ib) or apharmaceutically acceptable salt or hydrate thereof.

The invention further relates to methods for treating or preventing areperfusion disease, comprising administering to an animal in needthereof an effective amount of a compound of formula (Ia) or (Ib) or apharmaceutically acceptable salt or hydrate thereof.

The invention further relates to methods for treating or preventinghyperuricemia, comprising administering to an animal in need thereof aneffective amount of a compound of formula (Ia) or (Ib) or apharmaceutically acceptable salt or hydrate thereof.

The invention further relates to methods for treating or preventingtumor-lysis syndrome, comprising administering to an animal in needthereof an effective amount of a compound of formula (Ia) or (Ib) or apharmaceutically acceptable salt or hydrate thereof.

The invention further relates to methods for treating or preventing aninflammatory bowel disorder, comprising administering to an animal inneed thereof an effective amount of a compound of formula (Ia) or (Ib)or a pharmaceutically acceptable salt or hydrate thereof.

The invention further relates to methods for inhibiting xanthine oxidaseactivity, comprising administering to an animal in need thereof aneffective amount of a compound of formula (Ia) or (Ib) or apharmaceutically acceptable salt or hydrate thereof.

The invention further relates to methods for treating or preventing aninflammation disease, comprising administering to an animal in needthereof an effective amount of a compound of formula (Ic):

or a pharmaceutically acceptable salt or hydrate thereof, wherein:

R₁ is -H, -CO₂R₄, -C(O)R₅, or -C(O)N(R₅)(R₅);

each R₂ is independently -halo, -NO₂, -CN, -OH, -N(R₅)(R₅), -OR₅,-C(O)R₅, -OC(O)R₅, -C(O)NHC(O)R₅, -(C₁-C₁₀)alkyl, -(C₂-C₁₀)alkenyl,-(C₂-C₁₀)alkynyl, -(C₃-C₁₀)cycloalkyl, -(C₈-C₁₄)bicycloalkyl,-(C₅-C₁₀)cycloalkenyl, -(C₃-C₁₀)heterocycle, -(C₅)heteroaryl,-(C₆)heteroaryl, -phenyl, -naphthyl, -benzyl, -CO₂R₅, -C(O)OCH(R₅)(R₅),-NHC(O)R₅, -NHC(O)NHR₅, -C(O)NHR₅, -OC(O)R₅, -OC(O)OR₅, -SR₅, -S(O)R₅,or -S(O)₂R₅;

R₃ is -H, -halo, -NO₂, -CN, -OH, -N(R₅)(R₅), -O(CH₂)_(m)R₅, -C(O)R₅,-C(O)N(R₅)(R₅), -C(O)NH(CH₂)_(m)(R₅), -OCF₃, -benzyl, -CO₂CH(R₅)(R₅),-(C₁-C₁₀)alkyl, -(C₂-C₁₀)alkenyl, -(C₂-C₁₀)alkynyl, -(C₃-C₁₀)cycloalkyl,-(C₈-C₁₄)bicycloalkyl, -(C₅-C₁₀)cycloalkenyl, -(C₅)heteroaryl,-(C₆)heteroaryl, -naphthyl, -(C₃-C₁₀)heterocycle, -CO₂(CH₂)_(m)R₅,-NHC(O)R₅, -N(R₅)C(O)R₅, -NHC(O)NHR₅, -OC(O)(CH₂)_(m) CHR₅R₅,-CO₂(CH₂)_(m)CHR₅R₅, -OC(O)OR₅, -SR₅, -S(O)R₅, -S(O)₂R₅, -S(O)₂NHR₅, or

R₄ is -CF₃, -(C₁-C₁₀)alkyl, -benzyl, -adamantyl, -morpholinyl,-pyrrolidyl, -pyrridyloxide, -pyrrolidinyldione, -piperdidyl,-(C₅)heteroaryl, -(C₆)heteroaryl, -(C₂-C₁₀)alkenyl, -(C₂-C₁₀)alkynyl,-(C₃-C₁₀)cycloalkyl, -(C₈-C₁₄)bicycloalkyl, -(C₃-C₁₀)heterocycle, or

each R₅ is independently -H or R₄;

each R₆ is independently -H, -halo, -NO₂, -CN, -OH, -CO₂H,-N((C₁-C₁₀)alkyl(C₁-C₁₀)alkyl), -O(C₁-C₁₀)alkyl, -C(O)(C₁-C₁₀)alkyl,-C(O)NH(CH₂)_(m)(C₁-C₁₀)alkyl, -OCF₃, -benzyl,-CO₂(CH₂)_(m)CH((C₁-C₁₀)alkyl(C₁-C₁₀)alkyl), -C(O)H, -CO₂(C₁-C₁₀)alkyl,-(C₁-C₁₀)alkyl, -(C₂-C₁₀)alkenyl, -(C₂-C₁₀)alkynyl, -(C₃-C₁₀)cycloalkyl,-(C₈-C₁₄)bicycloalkyl, -(C₅-C₁₀)cycloalkenyl, -(C₅)heteroaryl,-(C₆)heteroaryl, -phenyl, naphthyl, -(C₃-C₁₀)heterocycle,-CO₂(CH₂)_(m)(C₁-C₁₀)alkyl, -CO₂(CH₂)_(m)H, -NHC(O)(C₁-C₁₀)alkyl,-NHC(O)NH(C₁-C₁₀)alkyl, -OC(O)(C₁-C₁₀)alkyl, -OC(O)O(C₁-C₁₀)alkyl,-SO₂NHR₅, or -SO₂NH₂;

n is an integer ranging from 0 to 4;

each m is independently an integer ranging from 0 to 8; and

each p is independently an integer ranging from 0 to 5.

The invention further relates to methods for treating or preventing areperfusion disease, comprising administering to an animal in needthereof an effective amount of a compound of formula (Ic) or apharmaceutically acceptable salt or hydrate thereof.

The invention further relates to methods for treating or preventinghyperuricemia, comprising administering to an animal in need thereof aneffective amount of a compound of formula (Ic) or a pharmaceuticallyacceptable salt or hydrate thereof.

The invention further relates to methods for treating or preventingtumor-lysis syndrome, comprising administering to an animal in needthereof an effective amount of a compound of formula (Ic) or apharmaceutically acceptable salt or hydrate thereof.

The invention further relates to methods for treating or preventing aninflammatory bowel disorder, comprising administering to an animal inneed thereof an effective amount of a compound of formula (Ic) or apharmaceutically acceptable salt or hydrate thereof.

The invention further relates to methods for inhibiting xanthine oxidaseactivity, comprising administering to an animal in need thereof aneffective amount of a compound of formula (Ic) or a pharmaceuticallyacceptable salt or hydrate thereof.

The invention also relates to kits comprising a container containing acompound of formula (Ia), (Ib), or (Ic) or a pharmaceutically acceptablesalt or hydrate thereof (each being a "5-Aryltetrazole Compound").

The invention can be understood more fully by reference to the followingdetailed description and illustrative examples, which are intended toexemplify non-limiting embodiments of the invention.

4. DETAILED DESCRIPTION OF THE INVENTION

4.1 DEFINITIONS

As used herein, the term "-(C₁-C₁₀)alkyl" means a saturated straightchain or branched non-cyclic hydrocarbon having from 1 to 10 carbonatoms. Representative saturated straight chain alkyls include -methyl,-ethyl, -n-propyl, -n-butyl, -n-pentyl, -n-hexyl, -n-heptyl, -n-octyl,-n-nonyl and -n-decyl; while saturated branched alkyls include-isopropyl, -sec-butyl, -isobutyl, -tert-butyl, -isopentyl,-2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl,5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl,2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl,2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl,3,3-dimtheylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl,3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl,2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl,2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl,2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl and3,3-diethylhexyl. In addition, chemical nomenclature used to definealkyl groups has its standard meaning known to those of ordinary skillin the art, for example, "Me" means methyl or -CH₃, "Et" means ethyl or-CH₂CH₃, "n-Pr" means n-propyl or -CH₂CH₂CH₃, "i-Pr" means iso-propyl or-CH(CH₃)₂, "n-Bu" means n-butyl or -CH₂(CH₂)₂CH₃, "t-Bu" meanstert-butyl or -C(CH₃)₃.

As used herein, the term "-(C₂-C₁₀)alkenyl" means a straight chain orbranched non-cyclic hydrocarbon having from 2 to 10 carbon atoms andincluding at least one carbon-carbon double bond. Representativestraight chain and branched (C₂-C₁₀)alkenyls include -vinyl, -allyl,-1-butenyl, -2-butenyl, -isobutylenyl, -1-pentenyl, -2-pentenyl,-3-methyl-1-butenyl, -2-methyl-2-butenyl, 2,3-dimethyl-2-butenyl,-1-hexenyl, -2-hexenyl, -3-hexenyl, -1-heptenyl, -2-heptenyl,-3-heptenyl, -1-octenyl, -2-octenyl, -3-octenyl, -1-nonenyl, -2-nonenyl,-3-nonenyl, -1-decenyl, -2-decenyl and -3-decenyl and the like.

As used herein, the term "-(C₂-C₁₀)alkynyl" means a straight chain orbranched non-cyclic hydrocarbon having from 2 to 10 carbon atoms andincluding at least one carbon-carbon triple bond. Representativestraight chain and branched -(C₂-C₁₀)alkynyls include -acetylenyl,-propynyl, -1-butynyl, -2-butynyl, -1-pentynyl, -2 pentynyl,-3-methyl-l-butynyl, -4-pentynyl, -1-hexynyl, -2-hexynyl, -5-hexynyl,-1-heptynyl, -2-heptynyl, -6-heptynyl, -1-octynyl, -2-octynyl,-7-octynyl, -1-nonynyl, -2-nonynyl, -8-nonynyl, -1-decynyl, -2-decynyland -9-decynyl and the like.

As used herein, the term "-(C₃-C₁₀)cycloalkyl" means a saturated cyclichydrocarbon having from 3 to 10 carbon atoms. Representative(C₃-C₁₀)cycloalkyls include -cyclopropyl, -cyclobutyl, -cyclopentyl,-cyclohexyl, -cycloheptyl, -cyclooctyl, -cyclononyl, and -cyclodecyl.

As used herein, the term "-(C₈-C₁₄)bicycloalkyl" means a bi-cyclichydrocarbon ring system having from 8 to 14 carbon atoms and at leastone saturated cyclic alkyl ring. Representative-(C₈-C₁₄)bicyclocycloalkyls include -indanyl,─1,2,3,4-tetrahydronaphthyl, -5,6,7,8-tetrahydronaphthyl and-perhydronaphthyl and the like.

As used herein, the term "-(C₅-C₁₀)cycloalkenyl" means a cyclicnonaromatic hydrocarbon having at least one carbon-carbon double bond inthe cyclic system and from 5 to 10 carbon atoms. Representative(C₅-C₁₀)cycloalkenyls include -cyclopentenyl, -cyclopentadienyl,-cyclohexenyl, -cyclohexadienyl, -cycloheptenyl, -cycloheptadienyl,-cycloheptatrienyl, -cyclooctenyl, -cyclooctadienyl, -cyclooctatrienyl,-cyclooctatetraenyl, -cyclononenyl, -cyclononadienyl, -cyclodecenyl and-cyclodecadienyl and the like.

As used herein, the term "-(C₃-C₁₀)heterocycle" or"-(C₃-C₁₀)heterocyclo" means a 3- to 10-membered monocyclic heterocyclicring which is either saturated, unsaturated non-aromatic, or aromatic. A3-membered -(C₃-C₇)heterocycle can contain up to 3 heteroatoms, and a 4-to 10-membered -C₃-C₁₀)heterocycle can contain up to 4 heteroatoms. Eachheteroatom is independently selected from nitrogen, which can bequaternized; oxygen; and sulfur, including sulfoxide and sulfone. The-(C₃-C₁₀)heterocycle may be attached via any heteroatom or carbon atom.Representative -(C₃-C₁₀)heterocycles include pyridyl, furyl, thiophenyl,pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl,isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,morpholinyl, pyrrolidinonyl, pyrrolidinyl, piperidinyl, piperazinyl,benzo[1,3]dioxolyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrindinyl,tetrahydropyrimidinyl, tetrahydrothiophenyl and tetrahydrothiopyranyl. Aheteroatom may be substituted with a protecting group known to those ofordinary skill in the art, for example, the hydrogen on a nitrogen maybe substituted with a tert-butoxycarbonyl group or the hydrogen on anoxygen may be substituted with a methoxymethyl.

As used herein, the term "-(C₅)heteroaryl" means an aromatic heterocyclering of 5 members, wherein at least one carbon atom of the ring isreplaced with a heteroatom such as, for example, nitrogen.Representative -(C₅)heteroaryls include furyl, thienyl, pyrrolyl,oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl,pyrazinyl, triazolyl and thiadiazolyl and the like.

As used herein, the term "-(C₆)heteroaryl" means an aromatic heterocyclering of 6 members, wherein at least one carbon atom of the ring isreplaced with a heteroatom such as, for example, nitrogen. One of the-(C₆)heteroaryl's rings contain at least one carbon atom. Representative(C₆)heteroaryls include pyridyl, pyridazinyl, pyrazinyl, triazinyl,tetrazinyl and pyrimidyl and the like.

As used herein, the term "-O(C₁-C₁₀)alkyl" means a saturated straightchain or branched non-cyclic hydrocarbon having from 1 to 10 carbonatoms. Representative saturated straight chain alkyls include -methyoxy,-ethyoxy, -n-propyloxy, -n-butyloxy, -n-pentyloxy, -n-hexyloxy,-n-heptyloxy, -n-octyloxy, -n-nonyloxy and -n-decyloxy; while saturatedbranched alkyls include -isopropyloxy, -sec-butyloxy, -isobutyloxy,-tert-butyloxy, -isopentyloxy, -2-methylbutyloxy, -3-methylbutyloxy,-2-methylpentyloxy, -3-methylpentyloxy, -4-methylpentyloxy,-2-methylhexyloxy, -3-methylhexyloxy, -4-methylhexyloxy,-5-methylhexyloxy, -2,3-dimethylbutyloxy, -2,3-dimethylpentyloxy,-2,4-dimethylpentyloxy, -2,3-dimethylhexyloxy, -2,4-dimethylhexyloxy,-2,5-dimethylhexyloxy, -2,2-dimethylpentyloxy, -2,2-dimethylhexyloxy,-3,3-dimtheylpentyloxy, -3,3-dimethylhexyloxy, -4,4-dimethylhexyloxy,-2-ethylpentyloxy, -3-ethylpentyloxy, -2-ethylhexyloxy,-3-ethylhexyloxy, -4-ethylhexyloxy, -2-methyl-2-ethylpentyloxy,-2-methyl-3-ethylpentyloxy, -2-methyl-4-ethylpentyloxy,-2-methyl-2-ethylhexyloxy, -2-methyl-3-ethylhexyloxy,-2-methyl-4-ethylhexyloxy, -2,2-diethylpentyloxy, -3,3-diethylhexyloxy,-2,2-diethyihexyloxy and -3,3-diethylhexyloxy. In addition, chemicalnomenclature used to define alkyloxy groups has its standard meaningknown to those of ordinary skill in the art, for example, "OMe" meansmethoxy, methoxyl, or -OCH₃, "OEt" means ethoxy, ethoxyl, or -OCH₂CH₃,"n-Opr" means n-propyloxy or -CH₂CH₂CH₃, "i-OPr" means iso-propyloxy or-OCH(CH₃)₂, "n-OBu" means n-butyloxy or -OCH₂(CH₂)₂CH₃, "t-OBu" meanstert-butyloxy or -OC(CH₃)₃.

As used herein, the term "-Halogen" or "-Halo" means -F, -Cl, -Br or -I.

As used herein, the term "animal," includes, but is not limited to, acow, monkey, chimpanzee, baboon, horse, sheep, pig, chicken, turkey,quail, cat, dog, mouse, rat, rabbit, guinea pig and human.

As used herein, the term "adamantyl" includes 1-adamantyl, 2-adamantyl,and 3-adamantyl.

As used herein, the term "naphthyl" includes 1-naphthyl and 2-naphthyl.

As used herein, the term "morpholinyl" includes N-morpholinyl,2-morpholinyl, and 3-morpholinyl.

As used herein, the term "pyrridyloxide" includes 2-pyrridyloxide,3-pyrridyloxide, and 4-pyrridyloxide.

As used herein, the term "pyrrolidinyldione" includes N-pyrrolidinyl-2,3-dione, N-pyrrolidinyl-2,4-dione, N-pyrrolidinyl-2,5-dione,N-pyrrolidinyl-3,5-dione, N-pyrrolidinyl-3,4-dione,2-pyrrolidinyl-3,4-dione, or 3-pyrrolidinyldione-2,4-dione, and3-pyrrolidinyl-2,5-dione.

As used herein, the term "piperdinyl" includes N-piperdinyl,2-piperdinyl, and 3-piperdinyl.

As used herein, the term "pharmaceutically acceptable salt," is a saltformed from an acid and a basic nitrogen group of one of the5-Aryltetrazole Compounds. Illustrative salts include, but are notlimited, to sulfate, citrate, acetate, oxalate, chloride, bromide,iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,lactate, salicylate, acid citrate, tartrate, oleate, tannate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,p-toluenesulfonate, and pamoate (i.e.,1,1'-methylene-bis-(2-hydroxy-3-naphthoate)) salts. The term"pharmaceutically acceptable salt" also refers to a salt prepared from a5-Aryltetrazole Compound having an acidic functional group, such as acarboxylic acid functional group, and a pharmaceutically acceptableinorganic or organic base. Suitable bases include, but are not limitedto, hydroxides of alkali metals such as sodium, potassium, and lithium;hydroxides of alkaline earth metal such as calcium and magnesium;hydroxides of other metals, such as aluminum and zinc; ammonia, andorganic amines, such as unsubstituted or hydroxy-substituted mono-, di-,or trialkylamines; dicyclohexylamine; tributyl amine; pyridine;N-methyl, N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy loweralkyl)-amines, such as N,N-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine and lysine, and the like.

As used herein, the term "pharmaceutically acceptable hydrate," is ahydrate formed from the association of one or more water molecules witha 5-Aryltetrazole Compound. The term "hydrate" includes a mono-hydrate,dihydrate, trihydrate and tetrahydrate, and the like.

As used herein in connection with a 5-Aryltetrazole Compound, the term"effective amount" means an amount effective for (a) treating orpreventing an inflammation disease, a reperfusion disease, orhyperuricemia; or (b) inhibiting xanthine oxidase activity.

4.2 COMPOUNDS OF FORMULA (Ia)

As stated above, the invention encompasses compounds of Formula (Ia):

and pharmaceutically acceptable salts and hydrates thereof, wherein R₁,R₂, R₃, and n are defined above for the compounds of formula (Ia).

In one embodiment n is 0.

In another embodiment n is 0 and R₃ is -halo.

In another embodiment n is 0 and R₃ is -C(O)R₅.

In another embodiment n is 0 and R₃ is -C(O)NHC(O)R₅.

In another embodiment n is 0 and R₃ is -C(O)N(R₅)(R₅).

In another embodiment n is 0 and R₃ is -CO₂(CH₂)_(m)(R₅).

In another embodiment n is 0 and R₃ is -H.

In another embodiment n is 0 and R₃ is -NHC(O)N(R₅)(R₅).

In another embodiment n is 0 and R₃ is -C(O)NHR₅.

In another embodiment n is 0; R₃ is -C(O)NHR₅; and R₅ is

.

In another embodiment n is 0; R₃ is -C(O)NHR₅; R₅ is

and p is an integer from 1 to 3.

In another embodiment n is 0; R₃ is -C(O)NHR₅; R₅ is

and p is 1 or 2.

In another embodiment n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1; and R₆ is in the para position.

In another embodiment n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1; and R₆ is in a meta position.

In another embodiment n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1; and R₆ is in an ortho position.

In another embodiment n is 0; R₃ is -C(O)NHR₅; R₅ is

and each R₆ is independently -halo.

In another embodiment n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; and each R₆ is independently -halo.

In another embodiment n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently halo; and one R₆ is in the paraposition and the other R₆ is in a meta position.

In another embodiment n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently halo; and one R₆ is in the paraposition and the other R₆ is in an ortho position.

In another embodiment n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently halo; and one R₆ is in an orthoposition and the other R₆ is in a meta position.

In another embodiment n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently halo; and each R₆ is in an orthoposition.

In another embodiment n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently halo; and each R₆ is in a metaposition.

Illustrative subclasses of the compounds of formula (Ia) have thefollowing formulas, wherein R₄ is -(C₅)heteroaryl, -(C₆)heteroaryl,phenyl, naphthyl, or benzyl:

Formula AA;

Formula AB;

Formula AC;

Formula AD;

Formula AE;

Formula AF;

Formula AG;

Formula AH;

Formula AI;

Formula AJ;

Formula AK;

Formula AL;

Formula AM;

Formula AN;

Formula AO;

Formula AP;

Formula AQ;

Formula AR;

Formula AS;

Formula AT;

Formula AU;

Formula AV;

Formula CM;

and pharmaceutically acceptable salts or hydrates thereof.

4.3 COMPOUNDS OF FORMULA (Ib)

The invention also encompasses compounds of Formula (Ib):

and pharmaceutically acceptable salts or hydrates thereof, wherein R₁and R₂ are defined above for the compounds of formula (Ib).

In one embodiment R₁ is -H.

In another embodiment R₁ is -H and R₂ is -(C₁ -C₁₀)alkyl.

In another embodiment R₁ is -H and R₂ is -O(C₁ -C₁₀)alkyl.

In another embodiment, R₁ is -H and R₂ is methyl.

In another embodiment, R₁ is -H and R₂ is ethyl.

In another embodiment, R₁ is -H and R₂ is n-propyl.

In another embodiment, R₁ is -H and R₂ is iso-propyl.

In another embodiment, R₁ is -H and R₂ is n-butyl.

In another embodiment, R₁ is -H and R₂ is iso-butyl.

In another embodiment, R₁ is -H and R₂ is sec-butyl.

In another embodiment, R₁ is -H and R₂ is tert-butyl.

In another embodiment, R₁ is -H and R₂ is n-pentyl.

In another embodiment, R₁ is -H and R₂ is isopentyl.

In another embodiment, R₁ is -H and R₂ is n-hexyl.

In another embodiment, R₁ is -H and R₂ is n-heptyl.

In another embodiment, R₁ is -H and R₂ is n-octyl.

In another embodiment, R₁ is -H and R₂ is n-nonyl.

In another embodiment, R₁ is -H and R₂ is n-decyl.

In another embodiment, R₁ is -H and R₂ is 2-methylbutyl.

In another embodiment, R₁ is -H and R₂ is 3-methylbutyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is methyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is ethyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-propyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is iso-propyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-butyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is iso-butyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is sec-butyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is tert-butyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-pentyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is isopentyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-hexyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-heptyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-octyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-nonyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-decyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is 2-methylbutyl.

In another embodiment, R₁ is -C(O)R₅ and R₂ is 3-methylbutyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is methyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is ethyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-propyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is iso-propyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-butyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is iso-butyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is sec-butyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is tert-butyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-pentyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is isopentyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-hexyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-heptyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-octyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-nonyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-decyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is 2-methylbutyl.

In another embodiment, R₁ is -CO₂R₄ and R₂ is 3-methylbutyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is methyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is ethyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-propyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is iso-propyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-butyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is iso-butyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is sec-butyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is tert-butyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-pentyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is isopentyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-hexyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-heptyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-octyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-nonyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-decyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is 2-methylbutyl.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is 3-methylbutyl.

In another embodiment, R₁ is -H and R₂ is methoxy.

In another embodiment, R₁ is -H and R₂ is ethoxy.

In another embodiment, R₁ is -H and R₂ is n-propyloxy.

In another embodiment, R₁ is -H and R₂ is iso-propyloxy.

In another embodiment, R₁ is -H and R₂ is n-butyloxy.

In another embodiment, R₁ is -H and R₂ is iso-butyloxy.

In another embodiment, R₁ is -H and R₂ is sec-butyloxy.

In another embodiment, R₁ is -H and R₂ is tert-butyloxy.

In another embodiment, R₁ is -H and R₂ is n-pentyloxy.

In another embodiment, R₁ is -H and R₂ is isopentyloxy.

In another embodiment, R₁ is -H and R₂ is n-hexyloxy.

In another embodiment, R₁ is -H and R₂ is n-heptyloxy.

In another embodiment, R₁ is -H and R₂ is n-octyloxy.

In another embodiment, R₁ is -H and R₂ is n-nonyloxy.

In another embodiment, R₁ is -H and R₂ is n-decyloxy.

In another embodiment, R₁ is -H and R₂ is 2-methylbutyloxy.

In another embodiment, R₁ is -H and R₂ is 3-methylbutyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is methoxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is ethoxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-propyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is iso-propyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-butyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is iso-butyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is see-butyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is tert-butyloxy.

In another embodiment, Rt is -C(O)R₅ and R₂ is n-pentyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is isopentyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-hexyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-heptyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-octyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-nonyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is n-decyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is 2-methylbutyloxy.

In another embodiment, R₁ is -C(O)R₅ and R₂ is 3-methylbutyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is methoxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is ethoxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-propyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is iso-propyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-butyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is iso-butyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is sec-butyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is tert-butyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-pentyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is isopentyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-hexyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-heptyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-octyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-nonyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is n-decyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is 2-methylbutyloxy.

In another embodiment, R₁ is -CO₂R₄ and R₂ is 3-methylbutyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is methyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is ethyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-propyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is iso-propyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-butyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is iso-butyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is sec-butyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is tert-butyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-pentyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is isopentyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-hexyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-heptyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-octyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-nonyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is n-decyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is 2-methylbutyloxy.

In another embodiment, R₁ is -C(O)N(R₅)(R₅) and R₂ is 3-methylbutyloxy.

Illustrative compounds of formula (Ib) are:

and pharmaceutically acceptable salts and hydrates thereof.

4.4 COMPOUNDS OF FORMULA (Ic)

As stated above, the present invention encompasses methods for treatingor preventing an inflammation disease, a reperfusion disease, orhyperuricemia comprising administering to an animal in need thereof aneffective amount of a compound of Formula (Ic):

or a pharmaceutically acceptable salt or hydrate thereof, wherein R₁,R₂, R₃ and n are defined above for the compounds of formula (Ic).

In one embodiment R₁ is -H.

In another embodiment R₁ is -H; n is 0; and R₃ is -(C₁-C₁₀)alkyl.

In another embodiment R₁ is -H; n is 0; and R₃ is -O(CH₂)_(m)R₅.

In another embodiment R₁ is -H; n is 0; R₃ is -O(CH₂)_(m)R₅; and R₅ is-H.

In another embodiment R₁ is -H; n is 0; and R₃ is -halo.

In another embodiment R₁ is -H; n is 0; and R₃ is -C(O)R₅.

In another embodiment R₁ is -H; n is 0; and R₃ is -C(O)NHC(O)R₅.

In another embodiment R₁ is -H; n is 0; and R₃ is -C(O)N(R₅)(R₅).

In another embodiment R₁ is -H; n is 0; and R₃ is -H.

In another embodiment R₁ is -H; n is 0; and R₃ is -CO₂(CH₂)_(m)(R₅).

In another embodiment R₁ is -H; n is 0; and R₃ is -NHC(O)N(R₅)(R₅).

In another embodiment R₁ is -H; n is 0; and R₃ is -C(O)NHR₅.

In another embodiment R₁ is -H; n is 0; R₃ is -C(O)NHR₅; and R₅ is

In another embodiment R₁ is -H; n is 0; R₃ is -C(O)NHR₅; and R₅ is

and p is an integer from 1 to 3.

In another embodiment R₁ is -H; n is 0; R₃ is -C(O)NHR₅; R₅ is

and p is 1 or 2.

In another embodiment R₁ is -H; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1; and R₆ is halo and is in the para position.

In another embodiment R₁ is -H; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1; and R₆ is halo and is in a meta position.

In another embodiment R₁ is -H; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1; and R₆ is halo and is in an ortho position.

In another embodiment R₁ is -H; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; and each R₆ is independently -halo.

In another embodiment R₁ is -H; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently -halo; and one R₆ is in the paraposition and the other R₆ is in a meta position.

In another embodiment R₁ is -H; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently -halo; and one R₆ is in the paraposition and the other R₆ is in an ortho position.

In another embodiment R₁ is -H; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; and one R₆ is in an ortho position and the other R₆ is in a metaposition.

In another embodiment, R₁ is -CO₂R₄.

In another embodiment R₁ is -CO₂R₄ and n is 0.

In another embodiment R₁ is -CO₂R₄; n is 0; and R₃ is -halo.

In another embodiment R₁ is -CO₂R₄; n is 0; and R₃ is -C(O)R₅.

In another embodiment R₁ is -CO₂R₄; n is 0; and R₃ is -C(O)NHC(O)R₅.

In another embodiment R₁ is -CO₂R₄; n is 0; and R₃ is -H.

In another embodiment R₁ is -CO₂R₄; n is 0; and R₃ is -CO₂(CH₂)_(m)(R₅).

In another embodiment R₁ is -CO₂R₄; n is 0; and R₃ is -NHC(O)N(R₅)(R₅).

In another embodiment R₁ is -CO₂R₄; n is 0; and R₃ is -C(O)N(R₅)(R₅).

In another embodiment R₁ is -CO₂R₄; n is 0; and R₃ is -C(O)NHR₅.

In another embodiment R₁ is -CO₂R₄; n is 0; R₃ is -C(O)NHR₅; and R₅ is

In another embodiment R₁ is -CO₂R₄; n is 0; R₃ is -C(O)NHR₅; R₅ is

and p is an integer from 1 to 3.

In another embodiment R₁ is -CO₂R₄; n is 0; R₃ is -C(O)NHR₅; R₅ is

and p is 1 or 2.

In another embodiment R₁ is -CO₂R₄; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1; and R₆ is halo and is in the para position.

In another embodiment R₁ is -CO₂R₄; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1, and R₆ is halo and is in a meta position.

In another embodiment R₁ is -CO₂R₄; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1, and R₆ is halo and is in an ortho position.

In another embodiment R₁ is -CO₂R₄; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; and each R₆ is independently -halo.

In another embodiment R₁ is -CO₂R₄; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently halo; and one R₆ is in the paraposition and the other R₆ is in a meta position.

In another embodiment R₁ is -CO₂R₄; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently halo; and one R₆ is in the paraposition and the other R₆ is in an ortho position.

In another embodiment R₁ is -CO₂R₄; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently halo; and one R₆ is in the orthoposition and the other R₆ is in a meta position.

In another embodiment R₁ is -C(O)R₅.

In another embodiment R₁ is -C(O)R₅; n is 0; and R₃ is -halo.

In another embodiment R₁ is -C(O)R₅; n is 0; and R₃ is -C(O)R₅,

In another embodiment R₁ is -C(O)R₅; n is 0; and R₃ is -C(O)NHC(O)R₅,

In another embodiment R₁ is -C(O)R₅; n is 0; and R₃ is -H.

In another embodiment R₁ is -C(O)R₅; n is 0; and R₃ is-CO₂(CH₂)_(m)(R₅).

In another embodiment R₁ is -C(O)R₅; n is 0; and R₃ is -NHC(O)N(R₅)(R₅).

In another embodiment R₁ is -C(O)R₅; n is 0; and R₃ is C(O)N(R₅)(R₅).

In another embodiment R₁ is -C(O)R₅; n is 0; and R₃ is -C(O)NHR₅.

In another embodiment R₁ is -C(O)R₅; n is 0; R₃ is -C(O)NHR₅; and R₅ is

In another embodiment R₁ is -C(O)R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

and p is an integer from 1 to 3.

In another embodiment R₁ is -C(O)R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

and p is 1 or 2.

In another embodiment R₁ is -C(O)R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1; and R₆ is halo and is in the para position.

In another embodiment R₁ is -C(O)R₅; n is 0; R₃ is -C(O)NHR₅, R₅ is

p is 1; and R₆ is halo and is in a meta position.

In another embodiment R₁ is -C(O)R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1; and R₆ is halo and is in an ortho position.

In another embodiment R₁ is -C(O)R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; and each R₆ is independently -halo.

In another embodiment R₁ is -C(O)R₅; n is 0; R₃ is -C(ONHR_(5;) R₅ is

p is 2; each R₆ is independently -halo; and one R₆ is in the paraposition and the other R₆ is in a meta position.

In another embodiment R₁ is -C(O)R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently -halo; and one R₆ is in the paraposition and the other R₆ is in an ortho position.

In another embodiment R₁ is -C(O)R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; and one R₆ is in an ortho position and the other R₆ is in a metaposition.

In another embodiment, R₁ is -C(O)NR₅R₅.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; and R₃ is -halo.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; and R₃ is -C(O)R₅.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; and R₃ is -C(O)NHC(O)R₅.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; and R₃ is -H.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; and R₃ is-CO₂(CH₂)R_(m)(R₅).

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; and R₃ is-NHC(O)N(R₅)(R₅).

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; and R₃ is-C(O)N(R₅)(R₅).

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; and R₃ is -C(O)NHR₅.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; R₃ is -C(O)NHR₅; and R₅is

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

and p is an integer from 1 to 3.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

and p is 1 or 2.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1; and R₆ is halo and is in the para position.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1; and R₆ is halo and is in a meta position.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 1; and R₆ is halo and is in an ortho position.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; and each R₆ is independently -halo.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently -halo; and one R₆ is in the paraposition and the other R₆ is in a meta position.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; each R₆ is independently -halo; and one R₆ is in the paraposition and the other R₆ is in an ortho position.

In another embodiment R₁ is -C(O)NR₅R₅; n is 0; R₃ is -C(O)NHR₅; R₅ is

p is 2; and one R₆ is in an ortho position and the other R₆ is in a metaposition.

In another embodiment, the compounds of formula (Ic) are the compoundsof formula (Ia) and pharmaceutically acceptable salts and hydratesthereof, above.

In another embodiment, the compounds of formula (Ic) are the compoundsof formula (Ib) and pharmaceutically acceptable salts and hydratesthereof, above.

Illustrative compounds of formula (Ic) are:

and pharmaceutically acceptable salts or hydrates thereof.

4.5 METHODS FOR MAKING THE 5-ARYLTETRAZOLE COMPOUNDS

The 5-Aryltetrazole Compounds can be made using conventional organicsynthesis and/or by the following illustrative methods. Generalprocedures for the synthesis of aryl tetrazoles are provided in, Butler,R.N., Comprehensive Heterocyclic Chemistry Vol. IV, pp. 664-668(Katritzky et al. eds., 1996).

4.5.1. METHOD A

The 5-Aryltetrazole Compounds of formula (Ic) wherein R₁ is -H can beobtained by contacting a compound of formula A with an azide (e.g.,sodium azide ("NaN₃")) at reflux, (e.g., about 100 °C), in the presenceof zinc bromide ("ZnBr₂") using water as a solvent as shown below inScheme A. Compounds of formula A can be obtained commercially (e.g.,commercially available from Sigma-Aldrich Co.,http://www.sigmaaldrich.com) or made readily by those skilled in theart. A representative procedure for obtaining a 5-AryltetrazoleCompounds of formula (Ic) from a substituted phenyl nitrite in thepresence of sodium azide is provided in Sharpless et al., J. Org. Chem.7945-7950 (2001).

A 5-Aryltetrazole Compound of formula (Ic) wherein R₁ is -CO₂R₄,-C(O)R₅, or -C(O)N(R₅)(R₅) can be obtained by contacting a5-Aryltetrazole Compound of formula (Ic), wherein R₁ is -H with an acylcompound (e.g., XCO₂R₄, XC(O)R₅, or XC(O)N(R₅)(R₅), wherein X is Br orCl) in triethylamine (NEt₃).

4.5.2. METHOD B

In another embodiment, a 5-Aryltetrazole Compounds of formula (Ic)wherein R₁ is H can be obtained by contacting a compound of formula Awith an azide, (e.g., azidotrimethylsilane ("TMSN₃")) and a catalyticamount of dibutyl tin oxide ("n-Bu₂SnO") in refluxing toluene as asolvent as shown below in Scheme B. Methods for obtaining tetrazolesfrom nitriles and TMSN₃ are provided in, for example, Curran et al.,Tetrahedron, 1999, 55, 8997-9006.

A 5-Aryltetrazole Compound of formula (Ic) wherein R₁ is -CO₂R₄,-C(O)R₅, or -C(O)N(R₅)(R₅) can be obtained by contacting a5-Aryltetrazole Compound of formula (Ic), wherein R₁ is -H with an acylcompound (e.g., XCO₂R₄, XC(O)R₅, or XC(O)N(R₅)(R₅), wherein X is Br orCl) in triethylamine (NEt₃). Where R₅ is -H, protecting group chemistrycan be used.

4.5.3. METHOD C

The 5-Aryltetrazole Compounds of formula (Ic) wherein R₁ is -H can beconverted to 5-Aryltetrazole compounds of formula (Ia) by contacting thecompound of formula (Ic) wherein R₁ is -H with an alkyl chlorocarbonateor carbonic acid anhydride under conditions suitable for the formationof a carbamate as shown in Scheme C. Methods for obtaining carbamatesfrom amines and carbonates are provided in, for example, Raucher et al., Synthetic Commun. 1985, 15, 1025. For example, illustrative compoundsAA-AZ, BA-BZ, CA-CZ, DA-DZ, EA-EGcan be made using this method.

4.5.4. METHOD D

In another embodiment, a 5-Aryltetrazole Compound of formula (Ib)wherein R₁ is -H can be obtained by contacting a compound of formula Bwith a 4-substituted aniline (e.g., 4-methylaniline or 4-methoxyaniline)to obtain a compound of formula D'. The compound of formula D' is thencontacted with azide, (e.g., azidotrimethylsilane ("TMSN₃")) and acatalytic amount of dibutyl tin oxide ("n-Bu₂SnO") in refluxing tolueneas a solvent as shown below in Scheme B. Methods for obtainingtetrazoles from nitriles and TMSN₃ are provided in, for example, Curranet al. (see, e.g., section 4.4.2, above).

To obtain a 5-Aryltetrazole Compound of formula (Ib) wherein R₁ is-CO₂R₄, -C(O)R₅, or -C(O)N(R₅)(R₅), a 5-Aryltetrazole Compound offormula (Ib) wherein R₁ is -H is contacted with an acyl derivative(e.g., XCO₂R₄, XC(O)R₅, or XC(O)N(R₅)(R₅), wherein X is Br or Cl) intriethylamine (NEt₃) to provide a 5-Aryltetrazole Compound of formula(Ib). Where R₅ is -H, protecting group chemistry can be used. Forexample, illustrative compounds EH-FE can be made using this method.

5-Aryltetrazole Compounds can have asymmetric centers and therefore canexist in particular enantiomeric and/or diastereomeric forms. A5-Aryltetrazole Compound can be in the form of an optical isomer or adiastereomer. Accordingly, the invention encompasses 5-AryltetrazoleCompounds and their uses as described herein in the form of theiroptical isomers, diastereomers, and mixtures thereof, including aracemic mixture.

In addition, one or more hydrogen, carbon or other atoms of a5-Aryltetrazole Compound can be replaced by an isotope of the hydrogen,carbon, or other atom. Such compounds, which are encompassed by thepresent invention, are useful as research and diagnostic tools inmetabolism pharmokinetic studies and binding assays.

4.6 PROPHYLACTIC AND/OR THERAPEUTIC USES OF THE 5-ARYLTETRAZOLECOMPOUNDS

In accordance with the invention, an effective amount of a5-Aryltetrazole Compound, or a pharmaceutical composition comprising aneffective amount of a 5-Aryltetrazole Compound, is administered to ananimal in need of treatment or prevention of an inflammation disease, areperfusion disease, or hyperuricemia. In one embodiment, an effectiveamount of a 5-Aryltetrazole Compound can be used to treat or prevent anycondition that is treatable or preventable by inhibiting xanthineoxidase. Examples of conditions that are treatable or preventable byinhibiting xanthine oxidase include, but are not limited to, aninflammation disease, a reperfusion disease, or hyperuricemia. Inanother embodiment, an effective amount of a 5-Aryltetrazole Compoundcan be used to treat or prevent an inflammation disease, a reperfusiondisease, or hyperuricemia.

Examples of inflammation diseases include, but are not limited to,chronic inflammatory disorders of the joints including arthritis, e.g.,rheumatoid arthritis and osteoarthritis; respiratory distress syndrome;inflammatory bowel disorders; and inflammatory lung disorders of the eyesuch as corneal dystrophy, trachoma onchocerciasis, uveitis, sympatheticophthalmitis, and endophthalmitis; inflammatory disorders of the gum,e.g., periodontitis and gingivitis; tuberculosis; leprosy; inflammatorydiseases of the kidney including glomerulonephritis and nephrosis;inflammatory disorders of the gym, e.g., periodontitis and gingivitis;tuberculosis; leprosy; inflammatory diseases of the kidney includingglomerulonephritis and nephrosis; inflammatory disorders of the skinincluding acne, sclerodermatitis, psoriasis, eczema, photoaging andwrinkles; inflammatory diseases of the central nervous system, includingAIDS-related neurodegeneration, stroke, neurotrauma, Alzheimer'sdisease, encephalomyelitis and viral or autoimmune encephalitis;autoimmune diseases including immunecomplex vasculitis, systemic lupuserythematosus (SLE); and inflammatory diseases of the heart such ascardiomyopathy.

Examples of inflammatory bowel disorders include, but are not limitedto, ileitis, including, but not limited to, ulcerative colitis,collagenous/microscopic colitis, and enterocolitis; Crohn's disease; andpouchitis.

Examples of reperfusion diseases include, but are not limited to, shockand sepsis. Shock can be septic shock, e.g. gram positivebacteria-mediated circulatory shock, gram negative bacteria-mediatedcirculatory shock, hemorrhagic shock, anaphylactic shock, shockassociated with systemic inflammation, shock associated withpro-inflammatory cytokines, and shock associated with systemicinflammatory response syndrome (SIRS). The 5-Aryltetrazole Compounds canalso be used to prevent or treat circulatory shock, such as shockoccurring as a result of gram negative and gram positive sepsis, trauma,hemorrhage, burn injury, anaphylaxis, cytokine immunotherapy, organfailure (particularly kidney or live failure), or systemic inflammatoryresponse syndrome. Other examples of reperfusion disease are diseasearising from cell or solid-organ transplantation, cardiopulmonary bypasssurgery, compartment syndrome, crush injury, splanchnic ischemiareperfusion, myocardial infarction and stroke.

Examples of hyperuricemia include, but are not limited to, gout;tumor-lysis syndrome; idiopathic hyperuricemia; hyperuricemia inheritedincluding, but not limited to, hyperuricemia due to PP-ribose-Psynthetase, overactivity; hypoxanthine-gaunine phophoribosyltransferasedeficiency; glucose-6-phosphate deficiency; Gierke's glycogen storagedisease; chronic hemolytic hyperuricemia including, but not limited to,erythroid, myeloid, and lymphoid proliferative hyperuricemia; renalmechanistic hyperuricemia including, but not limited to, familialprogressive renal insufficiency, acquired chronic renal insufficiency,drug related renal insufficiency, and endogenous renal productiondisorders.

Examples of tumor-lysis syndrome include, but are not limited to,tumore-lysis syndrome resulting from chemotherapy treatment in patientswith cancer, including but not limited to, leukemias, lymphomas, smallcell lung cancer, and breast cancer. In one embodiment, the tumor-lysissyndrome is that which results from chemotherapy, particularly fortreating cancer.

4.7 METHODS FOR ADMINISTRATION

Due to their activity, the 5-Aryltetrazole Compounds are advantageouslyuseful in veterinary and human medicine. As described above, the5-Aryltetrazole Compounds are useful for treating or preventing aninflammation disease, a reperfusion disease, or hyperuricemia.

When administered to an animal, an effective amount of a 5-AryltetrazoleCompound can be administered as a component of a composition thatcomprises a pharmaceutically acceptable carrier or vehicle. The presentcompositions, which comprise a 5-Aryltetrazole Compound, are in oneembodiment administered orally. The compositions of the invention canalso be administered by any other convenient route, for example, byinfusion or bolus injection, by absorption through epithelial ormucocutaneous linings (e.g., oral mucosa, rectal, and intestinal mucosa,etc.) and may be administered together with another therapeutic agent.Administration can be systemic or local. Various delivery systems areknown, e.g., encapsulation in liposomes, microparticles, microcapsules,capsules, etc., and can be used to administer the 5-AryltetrazoleCompounds.

Methods of administration include, but are not limited to, intradermal,intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal,epidural, oral, sublingual, intracerebral, intravaginal, transdermal,rectally, by inhalation, or topically, particularly to the ears, nose,eyes, or skin. The mode of administration is left to the discretion ofthe practitioner. In most instances, administration will result in therelease of the 5-Aryltetrazole Compounds into the bloodstream.

In specific embodiments, it may be desirable to administer the5-Aryltetrazole Compounds locally. This may be achieved, for example,and not by way of limitation, by local infusion during surgery, topicalapplication, e.g., in conjunction with a wound dressing after surgery,by injection, by means of a catheter, by means of a suppository, or bymeans of an implant, said implant being of a porous, non-porous, orgelatinous material, including membranes, such as sialastic membranes,or fibers.

In certain embodiments, it may be desirable to introduce the5-Aryltetrazole Compounds into the central nervous system by anysuitable route, including intraventricular, intrathecal, and epiduralinjection. Intraventricular injection may be facilitated by anintraventricular catheter, for example, attached to a reservoir, such asan Ommaya reservoir.

Pulmonary administration can also be employed, e.g., by use of aninhaler or nebulizer, and formulation with an aerosolizing agent, or viaperfusion in a fluorocarbon or synthetic pulmonary surfactant. Incertain embodiments, the 5-Aryltetrazole Compounds can be formulated asa suppository, with traditional binders and excipients such astriglycerides.

In another embodiment, the 5-Aryltetrazole Compounds can be delivered ina vesicle, in particular a liposome (see Langer, Science 249:1527-1533(1990) and Treat et al., Liposomes in the Therapy of Infectious Diseaseand Cancer 317-327 and 353-365 (1989).

In yet another embodiment, the 5-Aryltetrazole Compounds can bedelivered in a controlled-release system (see, e.g., Goodson, in MedicalApplications of Controlled Release, supra, vol. 2, pp. 115-138 (1984)).Other controlled-release systems discussed in the review by Langer,Science 249:1527-1533 (1990) may be used. In one embodiment, a pump maybe used (Langer, Science 249:1527-1533 (1990); Sefton, CRC Crit. Ref.Biomed. Eng. 14:201 (1987); Buchwald et al., Surgery 88:507 (1980); andSaudek et al., N. Engl. J. Med. 321:574 (1989)). In another embodiment,polymeric materials can be used (see Medical Applications of ControlledRelease (Langer and Wise eds., 1974); Controlled Drug Bioavailability,Drug Product Design and Performance (Smolen and Ball eds., 1984); Rangerand Peppas, J. Macromol. Sci. Rev. Macromol. Chem. 23:61 (1983); Levy etal., Science 228:190 (1985); During et al., Ann. Neurol. 25:351 (1989);and Howard et al., J. Neurosurg. 71:105 (1989)). In yet anotherembodiment, a controlled-release system can be placed in proximity of atarget of the 5-Aryltetrazole Compound, e.g., the spinal column orbrain, thus requiring only a fraction of the systemic dose.

The present compositions can optionally comprise a suitable amount of apharmaceutically acceptable carrier or vehicle so as to provide the formfor proper administration to the animal.

Such pharmaceutical carriers or vehicles can be liquids, such as waterand oils, including those of petroleum, animal, vegetable, or syntheticorigin, such as peanut oil, soybean oil, mineral oil and sesame oil. Thepharmaceutical vehicles can be saline, gum acacia, gelatin, starchpaste, talc, keratin, colloidal silica and urea. In addition, auxiliary,stabilizing, thickening, lubricating, and coloring agents may be used.When administered to a animal, the pharmaceutically acceptable carriersor vehicles are preferably sterile. Water is a particularly usefulvehicle when the 5-Aryltetrazole Compound of the invention isadministered intravenously. Saline solutions and aqueous dextrose andglycerol solutions can also be employed as liquid excipients,particularly for injectable solutions. Suitable pharmaceuticalexcipients also include starch, glucose, lactose, sucrose, gelatin,malt, rice, flour, chalk, silica gel, sodium stearate, glycerolmonostearate, talc, sodium chloride, dried skim milk, glycerol,propylene, glycol, water and ethanol. The present compositions, ifdesired, can also contain minor amounts of wetting or emulsifyingagents, or pH buffering agents.

The present compositions can take the form of solutions, suspensions,emulsion, tablets, pills, pellets, capsules, capsules containingliquids, powders, sustained-release formulations, suppositories,emulsions, aerosols, sprays, suspensions, or any other form suitable foruse. In one embodiment, the composition is in the form of a capsule (seee.g., U.S. Patent No. 5,698,155). Other examples of suitablepharmaceutical excipients are described in Remington's PharmaceuticalSciences 1447-1676 (Alfonso R. Gennaro ed., 19th ed. 1995), incorporatedherein by reference.

In one embodiment, the 5-Aryltetrazole Compounds are formulated inaccordance with routine procedures as a composition adapted for oraladministration to human beings. Compositions for oral delivery may be inthe form of tablets, lozenges, aqueous or oily suspensions, granules,powders, emulsions, capsules, syrups, or elixirs, for example. Orallyadministered compositions may contain one or more agents, for example,sweetening agents such as fructose, aspartame or saccharin; flavoringagents such as peppermint, oil of wintergreen, or cherry; coloringagents; and preserving agents, to provide a pharmaceutically palatablepreparation. Moreover, where in tablet or pill form, the compositionscan be coated to delay disintegration and absorption in thegastrointestinal tract thereby providing a sustained action over anextended period of time. Selectively permeable membranes surrounding anosmotically active driving compound are also suitable for orallyadministered compositions. In these later platforms, fluid from theenvironment surrounding the capsule is imbibed by the driving compound,which swells to displace the agent or agent composition through anaperture. These delivery platforms can provide an essentially zero orderdelivery profile as opposed to the spiked profiles of immediate releaseformulations. A time delay material such as glycerol monostearate orglycerol stearate may also be used. Oral compositions can includestandard excipients such as mannitol, lactose, starch, magnesiumstearate, sodium saccharin, cellulose and magnesium carbonate. Suchexcipients are preferably of pharmaceutical grade.

In another embodiment, the 5-Aryltetrazole Compounds can be formulatedfor intravenous administration. Typically, compositions for intravenousadministration comprise sterile isotonic aqueous buffer. Wherenecessary, the compositions may also include a solubilizing agent.Compositions for intravenous administration may optionally include alocal anesthetic such as lignocaine to lessen pain at the site of theinjection. Generally, the ingredients are supplied either separately ormixed together in unit dosage form, for example, as a dry lyophilizedpowder or water free concentrate in a hermetically sealed container suchas an ampoule or sachette indicating the quantity of active agent. Wherethe 5-Aryltetrazole Compounds are to be administered by infusion, theycan be dispensed, for example, with an infusion bottle containingsterile pharmaceutical grade water or saline. Where the 5-AryltetrazoleCompounds are administered by injection, an ampoule of sterile water forinjection or saline can be provided so that the ingredients may be mixedprior to administration.

The 5-Aryltetrazole Compounds of the invention can be administered bycontrolled-release means or by delivery devices that are well known tothose of ordinary skill in the art. Examples include, but are notlimited to, those described in U.S. Patent Nos.: 3,845,770; 3,916,899;3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767;5,120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,566, each of whichis incorporated herein by reference. Such dosage forms can be used toprovide slow or controlled-release of one or more active ingredientsusing, for example, hydropropylmethyl cellulose, other polymer matrices,gels, permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, microspheres, or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, can be readily selected for usewith the active ingredients of the invention. The invention thusencompasses single unit dosage forms suitable for oral administrationsuch as, but not limited to, tablets, capsules, gelcaps, and capletsthat are adapted for controlled-release.

The amount of the 5-Aryltetrazole Compound that is effective in thetreatment or prevention of can be determined by standard clinicaltechniques. In addition, in vitro or in vivo assays may optionally beemployed to help identify dosage ranges. The effective amount to beemployed will also depend on the route of administration, and theseriousness of and can be decided according to the judgment of thepractitioner and each patient's circumstances. Administration can be atan effective amount ranging from about 0.1 to about 500 mg/kg/day of the5-Aryltetrazole Compound to animal in need thereof. Suitable effectiveamounts can range from about 0.1 milligrams to about 500 milligramsabout every 4 h, although typically about 100 mg or less. In oneembodiment the effective amounts range from about 0.01 milligrams toabout 500 milligrams of a 5-Aryltetrazole Compound about every 4 h, inanother embodiment about 0.020 milligrams to about 50 milligrams aboutevery 4 h, and in another embodiment about 0.025 milligrams to about 20milligrams about every 4 h. The effective amounts described herein referto total amounts administered; that is, if more than one 5-AryltetrazoleCompound is administered, the effective amounts correspond to the totalamount administered.

The 5-Aryltetrazole Compounds can be assayed in vitro or in vivo, forthe desired therapeutic or prophylactic activity, prior to use inhumans. Animal model systems can be used to demonstrate safety andefficacy.

The present methods for treating or preventing inflammation disease, areperfusion disease, or hyperuricemia in an animal in need thereof canfurther comprise administering to the animal being administered a5-Aryltetrazole Compound and effective amount of another therapeuticagent.

Effective amounts of the other therapeutic agents are well known tothose skilled in the art. However, it is well within the skilledartisan's purview to determine the other therapeutic agent's optimaleffective-amount range. In one embodiment of the invention where anothertherapeutic agent is administered to an animal, the effective amount ofthe 5-Aryltetrazole Compound is less than its effective amount would bewhere the other therapeutic agent is not administered. In anotherembodiment, the 5-Aryltetrazole Compound and the other therapeutic agentact synergistically to treat an inflammation disease, a reperfusiondisease, or hyperuricemia. It is to be understood that where the methodscomprise administering an effective amount of a 5-Aryltetrazole Compoundand another therapeutic agent, the 5-Aryltetrazole Compound isadministered when the other therapeutic agent exerts its therapeuticeffect, or the other therapeutic agent is administered when the5-Aryltetrazole Compound exerts its therapeutic or prophylactic effect.

The other therapeutic agent can be a non-steroidal anti-inflammatoryagent. Useful non-steroidal anti-inflammatory agents, include, but arenot limited to, aspirin, ibuprofen, diclofenac, naproxen, benoxaprofen,flurbiprofen, fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen,carprofen, oxaproxin, pramoprofen, muroprofen, trioxaprofen, suprofen,aminoprofen, tiaprofenic acid, fluoprofen, bucloxic acid, indomethacin,sulindac, tolmetin, zomepirac, tiopinac, zidometacin, acemtacin,fentiazac, clidanac, oxpinac, mefenamic acid, flufenamic acid, niflumicacid, meclofenamic acid, flufenamic acid, niflumic acid, tolfenamicacid, diflurisal, flufenisal, piroxicam, sudoxicam, isoxicam; salicylicacid derivatives, including aspirin, sodium salicylate, cholinemagnesium trisalicylate, salsalate, diflunisal, salicylsalicylic acid,sulfasalazine, and olsalazin; par-aminophennol derivatives includingacetaminophen and phenacetin; indole and indene acetic acids, includingindomethacin, sulindac, and etodolac; heteroaryl acetic acids, includingtolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates),including mefenamic acid, and meclofenamic acid; enolic acids, includingoxicams (prioxicam, tenoxicam), and pyrazolidinediones (phenylbutazone,oxyphenthartazone); and alkanones, including nabumetone andpharmaceutically acceptable salts thereof and mixtures thereof. For amore detailed description of the NSAIDs, see Paul A. Insel,Analgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed inthe Treatment of Gout, in Goodman & Gilman's The Pharmacological Basisof Therapeutics 617-57 (Perry B. Molinhoff and Raymond W. Ruddon eds.,9^(th) ed 1996) and Glen R. Hanson, Analgesic, Antipyretic andAnti-Inflammatory Drugs in Remington: The Science and Practice ofPharmacy Vol II 1996-1221 (A. R. Gennaro ed. 19^(th) ed. 1995) which areherby incorporated by reference in there entireties.

The other therapeutic agent can be an anticonvulsant. Usefulanticonvulsants include, but are not limited to, acetylpheneturide,albutoin, aloxidone, aminoglutethimide, 4-amino-3-hydroxybutyric acid,atrolactamide, beclamaide, buramate, calcium bromide, carbamazepine,cinromide, clomethiazole, clonazepam, decimemide, diethadione,dimethadione, doxenitroin, eterobarb, ethadione, ethosuximide, ethotoin,felbamate, fluoresone, gabapentin, 5-hydroxytryptophan, lamotrigine,magnesium bromide, magnesium sulfate, mephenyloin, mephobarbital,methabital, methtoin, methsuximide, 5-methyl-5-(3-henanthryl)-hydantoin,3-methyl-5-phenylhydantoin, narcobarbital, nimetazepam, nitrazepam,oxcabazepine, paramethadione, phenacemide, phenetharbital, pheneturide,Phenobarbital, phensuzimide, phenylmethylbarbituric acid, phenyloin,phethenylate sodiyum, potassium bromide, pregabaline, primodone,progabide, sodium bromide, pregabaline, primodone, progabide, sodiumbromide, slanum, strontium bromide, suclofenide, sulthiame, tetrantoin,tiagabine, topiramate, tirmethadione, balproic acide, balpromide,vigabatrin, and zonisamide.

The other therapeutic agent can be an anti-depressant. Usefulantidepressants include, but are not limited to, binedaline, caroxazone,citalopram, dimethazan, fencamine, indalpine, indeloxazinehydrochloride, nefopam, nomifensine, oitriptan, oxypertine, paroxetine,sertaline, thiazesim, trazodone, benmoxine, iproclozide, iproniazid,isocarboxazid, nialamide, octamoxin, phenlzine, ocntinine, rolicyprine,rolipram, maprotiline, metralindole, mianserin, mirtazepine, adinazolam,amitriptyline, amitriptylinoxide, amoxapine, butriptyline, clomipramine,dothiepin, doxepin, flacizine, imipramine, imipramine N-oxide,iprindole, iofepramine, melitracen, metapramine, nortriptyline,noxipitilin, opipramol, pizotyline, propizepine, protriptyline,quinupramine, tianeptine, trimipramine, adrafinil benactyzine,burpropion, butacetin, dioxadrol, duloxetine, etoperidone, febarbamate,femoxetine, fenpentadiol, fluoxetine, fluvoxamine, hematoporphyrin,hypericin, levophacetoperane, mediofamine, milnacipran, minaprine,moclobemide, nefazodone, oxalozane, piberaline prolintane,pyrisuccideanol, ritanserin, roxindol, rubidium choloride, sulpride,tandospirone, thozalinone, tofenacin, toloxatone, tranylcypromine,L-tryptophan, venlafaxine, violoxazine, and zimeldine.

The other therapeutic agent can be an anti-hyperuricemic agent. Usefulanti-hyperuricemic agents also include, but are not limited to,allopurinol.

The other therapeutic agent can be an agent useful in treating orpreventing tumor-lysis syndrome. Therapeutic agents useful for treatingor preventing tumor-lysis syndrome also include, but are not limited to,Lasix or Zyloprim

The other therapeutic agent can be an agent useful in treating orpreventing an inflammatory bowel disorder. Therapeutic agents useful fortreating or preventing an inflammatory bowel disorder include, but arenot limited to, sulfasalazine, olsalazine, and mesalamine.

A 5-Aryltetrazole Compound and the other therapeutic agent can actadditively or, more preferably, synergistically. In one embodiment, a5-Aryltetrazole Compound is administered concurrently with anothertherapeutic agent. In one embodiment, a composition comprising aneffective amount of a 5-Aryltetrazole Compound and effective amount ofanother therapeutic agent can be administered. Alternatively, acomposition comprising an effective amount of a 5-Aryltetrazole Compoundand a different composition comprising an effective amount of anothertherapeutic agent can be concurrently administered. In anotherembodiment, an effective amount of a 5-Aryltetrazole Compound isadministered prior or subsequent to administration of an effectiveamount of another therapeutic agent.

4.8 KITS

The invention encompasses kits that can simplify the administration of a5-Aryltetrazole Compound to an animal.

A typical kit of the invention comprises a unit dosage form of a5-Aryltetrazole Compound. In one embodiment, the unit dosage form is acontainer, which can be sterile, containing an effective amount of a5-Aryltetrazole Compound and a pharmaceutically acceptable carrier orexcipient. The kit can further comprise a label or printed instructionsinstructing the use of the 5-Aryltetrazole Compound to treat or prevent.The kit can also further comprise a unit dosage form of anothertherapeutic agent, for example, a container containing an effectiveamount of the other therapeutic agent. In one embodiment, the kitcomprises a container containing an effective amount of a5-Aryltetrazole Compound and an effective amount of another therapeuticagent. Examples of other therapeutic agents include, but are not limitedto, those listed above.

Kits of the invention can further comprise devices that are useful foradministering the unit dosage forms. Examples of such devices include,but are not limited to, syringes, drip bags, patches, enema bags, andinhalers.

The following examples are set forth to assist in understanding theinvention and should not, of course, be construed as specificallylimiting the invention described and claimed herein. Such variations ofthe invention, including the substitution of all equivalents now knownor later developed, which would be within the purview of those skilledin the art, and changes in formulation or minor changes in experimentaldesign, are to be considered to fall within the scope of the inventionincorporated herein.

5. EXAMPLES

5.1 EXAMPLE 1

SYNTHESIS OF COMPOUND IC

A solution of 4-cyanobenzoylchloride B (0.82 g, 5 mmol) (commerciallyavailable from Sigma-Aldrich Co., http://www.sigmaaldrich.com) wasstirred in dry toluene (20 mL). Aniline (0.5 mL, 0.55 mmol) was addeddropwise, and following the initial exothermic reaction, the suspensionwas refluxed for 2 h. After cooling to room temperature, hexane (100 mL)was added to the reaction mixture and the precipitate was filtered andwashed with hexane to afford Compound D: Yield 2.0 g (90 %), ¹H NMR(DMSO-D₆): δ 7.1 (t, 1H, p-H-NHPh) 7.35 (t, 2H, m-H, NHPh), 7.75 (d, 2H,o-H, NHPh), 8.15 (AA'BB', Δ=27 Hz, 4H, C(O)Ar), 10.45 (s, 1H, C(O)NH).

A mixture of Compound D (2.2 g, 10 mmol), azidotrimethylsilane (2 mL, 15mmol) and dibutyltin oxide (0.5 g, 2 mmol) in anhydrous toluene (40 mL)was heated at 100°C for 5 h. The progress of the reaction was monitoredby Thin-Layer Chromatography. After completion of the reaction theorganic phase was extracted with 1 M NaOH (20 mL). The aqueous layer waswashed with ethyl acetate (2 x 20 mL) and acidified to pH 2 using 2 MHCl. The separated white solid was collected by filtration to provideCompound IC: Yield 1.95 g (75 %). ¹H NMR (DMSO-D₆): δ 5 7.1 (t, 1H, p-H,NHPh) 7.35 (t, 2H, m-H, NHPh), 7.8 (d, 2H, o-H, NHPh); 8.15 (AA'BB',Δ=12 Hz, 4H, C(O)Ar), 10.4 (s, 1H, C(O)NH). ES/MS: m/z⁺ 263 (M⁺ + 1, 100%).

5.2 EXAMPLE 2

ALTERNATIVE SYNTHESIS OF COMPOUND IC

A mixture of Compound D (2.2 g, 10 mmol), sodium azide (1.3 g, 20 mmol),zinc bromide (1.15 g, 10 mmol) and isopropanol (5 mL) in water (20 mL)was stirred at reflux for 48 h. After the mixture was cooled to 60° C,50 mL of 2 M NaOH was added and the suspension was stirred foradditional 30 min at this temperature. The precipitate was filtered andthe aqueous solution was extracted with ethyl acetate (2 x 50 mL). Theaqueous layer was separated and acidified to pH 2 using 2 M HCl. Theprecipitate was filtered and washed thoroughly with water to provideCompound IC. Yield 1.3 g (50 %).

Experimental data for illustrative 5-Aryltetrazoles Compounds preparedusing the methods analogous to those above are given below.

5.3 EXAMPLE 3

COMPOUNDS FT, HA-HC, HK, HL, HS, HT, HW-IM, IO, IP, IS, IX-JA, JG-JI,AND JK-JO

Compounds FT, HA-HC, HK, HL, HS, HT, HW-IF, IH-IM, IO, IS, IX-JA, JG-JI,and JK-JN were prepared according to the method of example 1 using thecorresponding amine in place of aniline. Compounds JO, IP, and IG wereprepared according to the method of examples 1 and 2 using thecorresponding amine in place of aniline.

Experimental data for illustrative 5-Aryltetrazoles Compounds preparedusing the method in Section 5.1 are given below.

Compound HX: ¹H NMR (DMSO-D₆): δ 7.2 (t, 2H, m-H, NHAr), 7.8 (q, 2H,o-H, NHAr), 8.05 (AA'BB', Δ = 10 Hz, 4H, C(O)Ar), 10.4 (s, 1H, C(O)NH).

Compound IA: ¹H NMR (DMSO-D₆): δ 2.6 (S, 3H, CH₃), 7.5 (d, 1H 3-H,NHAr), 7.7 (d, 1H, 4-H, NHAr), 8.1 (m, 5H, 2-H NAr+C(O)Ar), 8.4 (s, 1H,6-H, NHAr), 10.6 (s, 1H, C(O)NH).

Compound IP: ¹H NMR (DMSO-D₆): δ 1.2 (d, 6H, 2CH₃), 2.8 (m, 1H,CH(CH₃)₂), 7.4 (AA'BB', Δ = 140 Hz, 4H, C(O)Ar), 8.05 (AA'BB', m, 4H,C(O)Ar), 10.6 (s, 1H, C(O)NH).

Compound IS: ¹H NMR (DMSO-D₆): δ 6 7.9 (s, 4H, NHAr), 8.1 (AA'BB', Δ =34 Hz, 4H, C(O)Ar), 10.6 (s, 1H, C(O)NH).

Compound JN: ¹H NMR (DMSO-D₆): δ 2.2 (s, 3H, CH₃), 7.4 (AA'BB', Δ = 154Hz, 4H, NHAr), 8.05 (AA'BB', Δ = 14 Hz, 4H, C(O)Ar), 10.3 (s, 1H,C(O)NH).

5.4 EXAMPLE 4

SYNTHESIS OF COMPOUNDS FV-FX, FZ-GZ, HO-HR, AND JQ

Compounds FV-FX, FZ-GZ, HO-HR, AND JQwere prepared according to Method B(described in Section 4.4 above) from the corresponding esters of4-cyanobenzoic acid. These esters were obtained from 4-cyanobenzoylchloride and an alcohol or a halide as described in Vogel's Textbook ofPractical Organic Chemistry 5th Ed., p. 695. Such alcohols and halidesare commercially available.

5.5 EXAMPLE 5

SYNTHESIS OF COMPOUNDS IN, IR, IV, IW, AND JB-JE

To a solution of 4-cyanophenol (1.2 g, 10 mmol) in dry DMF (20 mL) wasadded triethylamine (20 mmol) followed by i-butyl bromide (2.7 g, 20mmol). The resulting reaction mixture was stirred at 100° C for 6 h.After cooling to room temperature, the reaction mixture was diluted withwater (100 mL) and extracted with ethyl acetate (2 x 40 mL). The organiclayer was washed with 4 M KOH (3 x 30 mL) and then with water, driedover Na₂SO₄ and concentrated under vacuum to provide 1.5 g (85%)4-iso-butoxybenzonitrile that was used for the next step without furtherpurification. ¹H NMR (DMSO-D₆): δ 0.95 (d, 6H, 2CH₃), 2.0 (m, 1H,CH(CH₃)₂), 3.8 (d, 2H, CH₂), 7.4 (AA'BB', Δ= 270 Hz, 4H, Ar).

A mixture of 4-iso-butoxybenzonitrile (1.75 g, 10 mmol),azidotrimethylsilane (2 mL, 15 mmol) and dibutyltinoxide (0.5 g, 2 mmol)in anhydrous toluene (40 mL) was heated at 100° C for 18 h. While stillhot, the organic phase was extracted with 20 mL 1 M NaOH, aqueous layerwas washed with ethyl acetate (2 x 20 mL) and acidified to pH 2 using 2M HCL. The resulting white solid was collected by filtration to provideCompound IR: Yield 1.2 g (55 %). ¹H NMR (DMSO-D₆): δ 0.95 (d, 6H, 2CH₃),2.0 (m, 1H, CH(CH₃)₂), 3.8 (d, 2H, CH₂), 7.5 (AA'BB', Δ= 295 Hz, 4H,Ar).

Compounds IN, IV, IW, JB, JC, and JDwere prepared analogously startingfrom the commercially available substituted 4-cyanophenols.3-Bromocyanophenol used in the synthesis of the compound JCwas preparedby bromination of 4-cyanophenol in acetic acid using bromine asdescribed in Minoshima et. al., JP 10139770 (1998). Compound JE wasprepared be reacting Compound JC with potassium cyanide in the presenceof catalytic amount of Ni[(PPh₃)₄] in N-methylpyrrolidone as describedin Minoshima et. al., JP 10139770 (1998).

5.6 EXAMPLE 6

COMPOUNDS FF-FQ, FU, FY, HE, HF, HG-HJ, HM, JP, AND JR

These compounds were obtained from the commercially availablesubstituted benzonitriles using the Method B.

5.7 EXAMPLE 7

COMPOUNDS OF FORMULA DL

Compounds of the Formula DL (R₄ = Bzl, Et, tert-Bu) were obtained fromCompound HE using Method C (described in Section 4.4), usingcommercially available CbzCl, ClCO₂Et, and Boc₂O, respectively.

5.8. EXAMPLE 8

COMPOUND FR

Compound FR was synthesized by reacting a commercially available4-aminobenzonitrile with acetic anhydride as described in Vogel'sTextbook of Practical Organic Chemistry 5th Ed., p. 917 and thenconverting a resulting 4-acetylaminobenzonitrile to Compound FRfollowingthe Method B.

5.9 EXAMPLE 9

COMPOUNDS FS AND IU

Compounds FSand IUwere synthesized by reacting 4-aminobenzonitrile withmethylisocyanate or phenylisocyanate, respectively, as described inVishnyakova et al., Russ. Chem. Rev., 1985, 54, 249 and then convertingthe resulting urea derivative to the respective 5-Aryltetrazole Compoundfollowing Method B.

5.10 EXAMPLE 10

COMPOUND HN

Compound HNwas prepared by reacting commercially available5-aminotetrazole with cinnamoyl chloride as described in Vogel'sTextbook of Practical Organic Chemistry 5 Ed., p. 917.

5.1 EXAMPLE 11

COMPOUNDS HU AND HV

Compounds HU and HV were prepared by reacting commercially available4-cyanobenzoylsulfonyl chloride with adamantyl amine andcyclohexylamine, respectively, and then converting a resulting amide toa tetrazole as described in Example 5.1 above.

5.12 EXAMPLE 12

COMPOUND IT

Compound ITwas prepared by benzoylation of 4-aminobenzonitrile asdescribed in Vogel's Textbook of Practical Organic Chemistry 5^(th) Ed.,p. 917 and then converting a resulting N-benzoyl-4-cyanoaniline toCompound ITfollowing the Method B (Sect. 4.4).

5.13 EXAMPLE 13

XANTHINE OXIDASE INHIBITORY ACTIVITY OF ILLUSTRATIVE 5-ARYL TETRAZOLECOMPOUNDS

A typical assay showing of xanthine oxidase inhibitory activity ofillustrative 5-Aryltetrazole Compounds involved the use of a 96 wellplate setup. Analysis of the sample utilized a Spectrophotometer with aSoftMax Pro Program set at a kinetic reading at a wavelength of 295 nmwith a runtime of 10 minutes taking a reading at 12 second intervals.Before the first reading the sample was mixed using an automixer forfive seconds and between readings the sample was mixed for threeseconds.

Sample Preparation: Approximately 1-2 mg of a 5-Aryltetrazole Compoundwas placed in a 5 mL, vial and dissolved in about 1 mL of DMSO resultingin a 2.5 mM solution.

Well Plate Preparation: Four to eight wells were used for each5-Aryltetrazole Compound. In each well was added 200 mL ofPhosphate-buffered saline (50 mM), 20 mL of xanthine (0.5 mg/mL inwater), 10 mL, of the 2.5 mM solution of 5-Aryltetrazole Compound(prepared as described above), and 20 mL of xanthine oxidase (1/100 x 40mL PBS). The xanthine oxidase was kept on ice and was added immediatelybefore the plate was run on the spectrophotometer. A control well wasalso prepared using only DMSO.

The following table shows concentrations of illustrative 5-AryltetrazoleCompounds providing xanthine-oxidase inhibition. Without being limitedby theory, compounds that inhibit xanthine oxidase are useful fortreating or preventing an inflammation disease, a reperfusion disease,or hyperuricemia.

PERCENT XANTHINE OXIDASE INHIBITION 5-Aryltetrazole CompoundConcentration (μM) Compound 100 10 1 0.1 0.05 0.03 0.01 FF 10 NT NT NTNT NT NT FG 34 NT NT NT NT NT NT FH 69 27 NT NT NT NT NT FI 67 21 NT NTNT NT NT FJ  7  5 NT NT NT NT NT FK 71 30 NT NT NT NT NT FL 55 14 NT NTNT NT NT FM 78 19 NT NT NT NT NT FM 32  3 NT NT NT NT NT FO 30  3 NT NTNT NT NT FP 21  3 NT NT NT NT NT FQ 99 81 34 NT NT NT NT FR 40 NT NT NTNT NT NT FS 10 NT NT NT NT NT NT FT 67 70 15 NT NT NT NT FU 92 54  9 NTNT NT NT FV 10 92 64 NT NT NT NT FW 10 82 39 NT NT NT NT FX 95 95 73 NTNT NT NT FY 91 56 11 NT NT NT NT FZ 10 97 88 NT NT NT NT GA 10 10 78 NTNT NT NT GB 10 97 82 NT NT NT NT GC NT NT 10 97 52 NT NT GD 10 82 79 NTNT NT NT GE NT NT 10 10 59 NT NT GF 97 79 28 NT NT NT NT GG 89 97 90 NTNT NT NT GH NT NT 10 91 NT 65 NT GI NT NT 10 95 NT 75 NT GJ NT NT 99 59NT NT 12 GK NT NT 46 12 NT NT  3 GL NT NT  4 NT NT NT NT GM NT NT 76 28NT NT  8 GN NT NT  9 NT NT NT NT GO NT NT 82 18 NT NT  6 GP NT NT 92 65NT NT  9 GQ NT NT 78 35 NT NT  0 GR NT NT 48  8 NT NT  0 GS NT NT 95 68NT NT 13 GT NT NT 94 53 NT NT  8 GU NT NT 94 69 NT NT 17 GV NT NT 95 73NT NT 14 GW NT NT 39  9 NT NT  5 GX NT NT 10 84 NT NT 19 GY NT NT 76 11NT NT 19 GZ NT NT  8 NT NT NT NT HA NT NT 61 10 NT NT NT HB NT NT 25 NTNT NT NT HC NT NT 25 NT NT NT NT HD 60 NT NT NT NT NT NT HE 33 NT NT NTNT NT NT HF 80 NT NT NT NT NT NT HG 22 NT NT NT NT NT NT HH 48 NT NT NTNT NT NT HI 70 24 14 NT NT NT NT HJ  2 NT NT NT NT NT NT HK 43 NT NT NTNT NT NT HL  0 NT NT NT NT NT NT HM 27 NT NT NT NT NT NT HN 42 13 10 NTNT NT NT HO NT NT 98 95 46 NT NT HP NT NT 10 91 41 NT NT HQ NT NT 95 9753 NT NT HR NT NT 95 95 34 NT NT HS NT NT 55 16 NT  8 NT HT NT NT 62 23NT 15 NT HU NT NT  0 NT NT NT NT HV NT NT  0 NT NT NT NT HW NT NT 89 62NT 32 NT HX NT NT 92 59 NT 37 NT HY NT NT 86 45 NT 20 NT HZ NT NT 88 41NT 20 NT IA NT NT 90 54 NT 31 NT IB NT NT 94 64 NT 38 NT IC NT NT 10 81NT 60 NT ID NT NT 72 37 NT 13 NT IE NT NT 87 38 NT 22 NT IF NT NT 16 NTNT NT NT IG NT NT 93 59 NT 33 NT IH NT NT 95 63 NT 33 NT II NT NT 90 45NT 20 NT IJ NT NT 93 58 NT 27 NT IK NT NT 55 17 NT  9 NT IL NT NT 86 46NT 21 NT IM NT NT  0 NT NT NT NT IN NT NT 68 21 NT NT NT IO NT NT  0 NTNT NT NT IP NT NT 92 52 NT 28 NT IQ NT NT 64 33 NT 36 NT IR NT NT 88 47NT 28 NT IS NT NT 97 68 NT 44 NT IT NT NT 56 15 NT  7 NT IU NT NT 42  9NT  3 NT IV NT NT 35 10 NT NT NT IW NT NT 22  9 NT NT NT IX NT NT 98 74NT 46 NT IY NT NT 86 47 NT 26 NT IZ NT NT 89 52 NT 23 NT JA NT NT NT  0NT NT NT JB NT NT 32 15 NT NT NT JC NT NT 31  6 NT NT NT JD NT NT 28  0NT NT NT JE NT NT 82 32 NT 12 NT JF NT NT 34  6 NT NT NT JG NT NT 93 61NT 33 NT JH NT NT 86 41 NT 23 NT JI NT NT 79 30 NT 19 NT JJ NT NT  0 NTNT NT NT JK NT NT  0 NT NT NT NT JL NT NT 95 68 NT 34 NT JM NT NT 89 38NT 16 NT JN NT NT 88 41 NT 20 NT JO NT NT 83 36 NT 18 NT JP NT NT 98 74NT 46 NT JQ NT NT 10 89 NT NT 18 JR 85 56 14 NT NT NT NT

The term "NT" means that the compound was not tested at the indicatedconcentration.

The above example demonstrates that Compounds FF-HK, HM-HT, HW-IL, IN,IP-IZ, JB-JI, and JL-JR, illustrative 5-Aryltetrazole Compounds, inhibitxanthine oxidase activity and, accordingly are useful for treating orpreventing an inflammation disease, a reperfusion disease, orhyperuricemia. In addition, Applicants believe that Compounds HL, HU,HV, IM, IO, JA, JJ, and JK, illustrative 5-Aryltetrazole Compounds, areuseful for treating or preventing an inflammation disease, a reperfusiondisease, or hyperuricemia.

5.14 EXAMPLE 14

Toxic Live Injury Model

Illustrative 5-Aryltetrazole Compounds exert hepatoprotective effects ina thioacetamide model of hepatic failure. The table below shows theefficacy of various illustrative 5-Aryltetrazole Compounds for theirhepatoprotective activity in mice. Illustrated are percent inhibition ofthe increased serum AST levels resulting from an intraperitonealinjection of thiacetamide (400 mg/kg) following a single oral dose(3mL/kg or 10 mL/kg) or various doses of 5-Aryltetrazole Compounds.Results are expressed as percent inhibition, mean ±SEM (n=7-10). Studieswere conducted as described in Biochim. Biphys. Acta. 1536(1): 21-30(2001).

TOXIC LIVER INJURY MODEL Percent Inhibition of Serum AST Levels Compound3 mg/kg 10 mg/kg IC  3 ± 8 20 ± 5 IG 25 ± 4 46 ± 8 IP 23 ± 8 41 ± 8 ISNT 33 ± 5 JM 12 ± 7 31 ± 7 JN 11 ± 7 31 ± 7 JO 24 ± 9  36 ± 12 IX NT 31± 1

Accordingly, the above example demonstrates that Compounds IC, IG, IP,IS, JM-JO, and IX, illustrative 5-Aryltetrazole Compounds, inhibit serumAST levels and, accordingly, are useful for treating or preventing organfailure.

5.15 EXAMPLE 15

Collagen-Induced Arthritis

An illustrative 5-Aryltetrazole Compound exerts protective effects in amodel of collagen-induce arthritis in mice. Results are expressed asincidence and severity over time. Studies were conducted as described inInflamm. Res. 50(11): 561-569 (2001). The results illustrate that theadministration of Compound JO, an illustrative 5-Aryltetrazole Compound,reduced incidence of collagen-induced arthritis in mice. Specifically,after 33 days 100% of the untreated mice exhibited arthritis; however,mice that were administered Compound JO showed a significant decrease inthe incidence of collagen-induced arthritis.

Time (days) 25 27 29 31 33 % Incidence 35 45 55 90 100 Vehicle CompoundJO 20 35 45 75 85 Mean Severity 0 0 8 10 12 Vehicle Compound JO 0 0 3 88

The above example demonstrates that Compound JO, an illustrative5-Aryltetrazole Compounds, inhibits collagen-induced arthritis andaccordingly, is useful for treating or preventing arthritis.

5.16 EXAMPLE 16

Reperfusion Injury

Illustrative 5-Aryltetrazole Compounds exert protective effects invarious models of organ ischemia and reperfusion. For example,intraperitoneal administration of illustrative 5-Aryltetrazole Compoundsretards the progression of gut ischemia reperfusion-inducedhyperpermeability and mortality in mice. Results are expressed as %decrease in gut hyperpermeability and as mortality as observed after 6hours and 2 days of reperfusion. Studies were conducted as described inShock, 24(2): 134-141 (2000). There was a notable dose-dependent effecton gut hyperpermeability and there was an improvement in survival rate,as tested at the highest dose of both levels.

Dose 3 mg/kg 10 mg/kg 30 mg/kg 30 mg/kg Compound Control IG IG IG JO Gut100% 73% 69% 47% 39% Permeability Dose 30 mg/kg 30 mg/kg CompoundControl IG JO Survival % (6 h) 60 87 87 Survival % (2 days)  0 20 13

The above example demonstrates that Compound IG and JO, illustrative5-Aryltetrazole Compounds, are useful for treating or preventing areperfusion disease in an animal.

The present invention is not to be limited in scope by the specificembodiments disclosed in the examples which are intended asillustrations of a few aspects of the invention and any embodiments thatare functionally equivalent are within the scope of this invention.Indeed, various modifications of the invention in addition to thoseshown and described herein will become apparent to those skilled in theart and are intended to fall within the scope of the appended claims.

A number of references have been cited, the entire disclosures of whichhave been incorporated herein in their entirety.

1. A compound being:

;

;

, or a pharmaceutically acceptable salt or hydrate thereof.
 27. Acomposition comprising an effective amount of a compound orpharmaceutically acceptable salt or hydrate of the compound of claim 26,and a pharmaceutically acceptable carrier or vehicle.